US20230322761A1 - Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use - Google Patents

Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use Download PDF

Info

Publication number
US20230322761A1
US20230322761A1 US17/910,037 US202117910037A US2023322761A1 US 20230322761 A1 US20230322761 A1 US 20230322761A1 US 202117910037 A US202117910037 A US 202117910037A US 2023322761 A1 US2023322761 A1 US 2023322761A1
Authority
US
United States
Prior art keywords
butyl
pyridin
compound according
tert
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US17/910,037
Other languages
English (en)
Inventor
Hexiang Wang
Bailin LEI
Changxin HUO
Dongqing SUN
Jie Chen
Zhiwei Wang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beigene Ltd
Original Assignee
Beigene Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beigene Ltd filed Critical Beigene Ltd
Assigned to BEIGENE, LTD. reassignment BEIGENE, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, JIE, HUO, Changxin, LEI, Bailin, SUN, Dongqing, WANG, ZHIWEI, WANG, HEXIANG
Publication of US20230322761A1 publication Critical patent/US20230322761A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • novel bifunctional compounds formed by conjugating BTK inhibitor moieties with E3 ligase Ligand moieties, which function to recruit targeted proteins to E3 ubiquitin ligase for degradation, and methods of preparation and uses thereof.
  • PROTAC Proteolysis-targeting chimera
  • the normal physiological function of the ubiquitin-protease system is responsible for clearing denatured, mutated, or harmful proteins in cells.
  • the ubiquitin-proteasome system also known as the ubiquitin-proteasome pathway (UPP)
  • UPS ubiquitin-proteasome pathway
  • UPS is a common posttranslational regulation mechanism that is responsible for protein degradation in normal and pathological states (Ardley H. et al., Essays Biochem. 2005, 41, 15-30; Komander D. et al., Biochem. 2012, 81, 203-229; Grice G. L. et al., Cell Rep. 2015, 12, 545-553; Swatek K. N. et al., Cell Res. 2016, 26, 399-422).
  • Ubiquitin which is highly conserved in eukaryotic cells, is a modifier molecule, composed of 76 amino acids, that covalently binds to and labels target substrates via a cascade of enzymatic reactions involving E1, E2, and E3 enzymes. Subsequently, the modified substrate is recognized by the 26S proteasome complex for ubiquitination-mediated degradation. So far, two E1 enzymes have been discovered, which are termed UBA1 and UBA6. On the other hand, there are about 40 E2 enzymes and more than 600 E3 enzymes that offer the functional diversity to govern the activity of many downstream protein substrates.
  • VHL Von Hippel-Lindau disease tumor suppressor protein
  • MDM2 Mouse Double Minute 2 homologue
  • cIAP Cellular Inhibitor of Apoptosis
  • cereblon Philipp O. et al., Chem. Biol. 2017, 12, 2570-2578.
  • Bifunctional compounds composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety have been shown to induce proteasome-mediated degradation of selected proteins. These drug-like molecules offer the possibility of temporal control over protein expression, and could be useful as biochemical reagents for the treatment of diseases. In recent years, this newly developed method has been widely used in antitumor studies (Lu J. et al., Chem Biol. 2015; 22(6):755-763; Ottis P. et al., Chem Biol. 2017; 12(4):892-898.; Crews C. M. et al., J Med Chem. 2018; 61(2):403-404; Neklesa T. K.
  • Btk Bruton's tyrosine kinase belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361: 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). Btk is primarily expressed in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al., J. Immunol. 152: 557-565, 1994) and is localized in bone marrow, spleen and lymph node tissue. Btk plays important roles in B-cell receptor (BCR) and FcR signaling pathways, which involve in B-cell development, differentiation (Khan, Immunol. Res.
  • BCR B-cell receptor
  • FcR FcR signaling pathways
  • Btk is activated by upstream Src-family kinases. Once activated, Btk, in turn, phosphorylates PLC gamma, leading to effects on B-cell function and survival (Humphries et al., J. Biol. Chem. 279: 37651, 2004). These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk cause an inherited B-cell specific immunodeficiency disease in humans, known as X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009).
  • XLA X-linked agammaglobulinemia
  • Btk inhibitors can be used to treat autoimmune and/or inflammatory diseases.
  • BTK has been shown to affect cancer development (B cell malignancies) and cell viability, and improve autoimmune diseases (e.g., rheumatoid arthritis and lupus). Inhibition of BTK has also been reported via alternative strategies, such as through degradation of BTK (Alexandru D. et al., Biochemistry 2018, 57, 26, 3564-3575; Adelajda Z. et al., PNAS 2018 115 (31); Dennis D., et al., Blood, 2019, 133:952-961; Yonghui S. et al., Cell Research, 2018, 28, 779-781; Yonghui S. et al., Leukemia, 2019, Degradation of Bruton's tyrosine kinase mutants by PROTACs for the potential treatment of ibrutinib-resistant non-Hodgkin lymphomas).
  • 3,5-disubstituted-1H-pyrazolo[3,4-b] pyridine can be new BTK inhibitors.
  • This application firstly describes that 3,5-disubstituted-1H-pyrazolo[3,4-b]pyridine can be a good BTK inhibitor, and can be used as PROTAC-derived degrader for BTK degradation.
  • One objective of the present invention is to provide a proteolysis targeting chimera (PROTAC) compound by conjugating a BTK inhibitor with an E3 ligase ligand, which functions to recruit targeted proteins to E3 ubiquitin ligase for degradation, and to provide a method of the preparation and uses thereof.
  • PROTAC proteolysis targeting chimera
  • the present disclosure provides PROTAC compounds with the Formula I.
  • Aspect 1 A compound of Formula (I):
  • u1 is an integral of 0-12; wherein * refers to the position attached to the
  • Aspect 2 The compound according to Aspect 1, wherein the Degron moiety is selected from Formulas D1, D2, D3, D4, D5, D6, D7 or D8:
  • Aspect 3 The compound according to Aspect 1, wherein Formula D1 is selected from
  • Aspect 4 The compound according to Aspect 14 wherein Formula D1 or D2 is selected from
  • Aspect 5 The compound according to Aspect 2, wherein Formula D1 D or D2 is selected from
  • Aspect 6 The compound according to Aspect 2, wherein Formula D3, D6 or D8 is selected from
  • R 8 is defined as above.
  • Aspect 7 The compound according to Aspect 6, wherein Formula D3, D6 or D8 is selected from
  • R 8 is halogen, —C 1-8 alkyl, or —C 1-8 alkoxy; preferably fluoro, chloro, methyl or methoxy.
  • Aspect 8 The compound according to Aspect 2, wherein Formula D4 is selected from
  • Aspect 9 The compound according to Aspect 8, wherein Formula D4 is selected from
  • Aspect 10 The compound according to any one of Aspects 1-9, where in the Linker is selected from a bond,
  • **1 refers to the position attached to the Degron
  • Aspect 11 The compound according to any one of Aspects 1-10, wherein the Linker is selected from
  • L 3 is —CH 2 —;
  • L 4 is —CH 2 CH 2 O— or —CH 2 —;
  • z 0, 1, 2, 3, 4, 5, 6, or 7;
  • L 6 is —CH 2 — or —NHC(O)—;
  • r 0, 1, 2, 3, or 4;
  • L 2 is —NH—, —CH 2 —, —O— or —C ⁇ C—.
  • Aspect 16 The compound according to Aspect 10, wherein the Linker is selected from
  • Aspect 21 The compound according to Aspect 16, wherein the Linker is selected from
  • Aspect 22 The compound according to Aspect 21, wherein
  • Aspect 23 The compound according to Aspect 10, wherein the Linker is selected from
  • Aspect 27 the compound according to Aspect 10, wherein the Linker is selected from
  • Aspect 28 the compound according to Aspect 10, wherein the Linker is selected from
  • Aspect 29 the compound according to Aspect 10, wherein the Linker is selected from
  • the Linker is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the Linker is —CH 2 -piperidin-4-yl, —CH 2 —CH 2 —CH 2 —O—, —CH 2 CH 2 —, a bond, —CH 2 CH 2 -piperidin-4-yl, or —C(O)—.
  • Aspect 31 The compound according to Aspect 1, wherein ring A is 5-membered aromatic ring comprising 1-3 heteroatoms selected from nitrogen and oxygen.
  • ring A is benzyl, oxadiazole, triazole, thiazole, or pyrazole, preferably, 1,2,4-oxadiazole-3-yl, 1,2,4-oxadiazole-5-yl, 1H-1,2,3-triazole-4-yl, or 1H-pyrazol-4-yl.
  • n is zero or one
  • L is a bond
  • R 3 is —C 1-8 alkyl or cycloalkyl, each optionally substituted with C 1-8 alkyl, halogen, hydroxyl-C 1-8 alkyl-, or -haloC 1-8 alkyl.
  • n is zero, L is a bond, and R 3 is C 3-4 alkyl or C 3-6 cyclopropyl, optionally substituted with halo, —CH 2 OH or -haloC 1-4 alkyl; preferably R 3 is tertbutyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-(trifluoromethyl)cyclopropyl, 1-methylcyclopropyl,2-hydroxyprapan-2-yl or 1-hydroxymethylcyclopropyl.
  • ring A is 5-tertbutyl-1,2,4-oxadiazole-3-yl, 3-tert butyl-1,2,4-oxadiazole-5-yl, 1-tertbutyl-1H-1,2,3-triazole-4-yl, 1-tertbutyl-1H-pyrazol-4-yl, 5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-yl, or 5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazole-3-yl.
  • Aspect 32 The compound according to Aspect 1, wherein L b is —(CR a R b ) u1 —NR 7 —C(O)—, or —C(O)—NR 7 —(CR a R b ) u1 —; wherein u1 is an integral of 0-12.
  • L b is *—C(O)—NR 7 —(CR a R b ) u1 —; wherein u1 is an integral of 1 or 2
  • R 7 , R a and R b is hydrogen or —C 1-8 alkyl, and the asterisk * refers to the position attached to Ring A.
  • L b is *—C(O)—NH—(CR a R b ) u1 —; wherein u1 is an integral of 1 or 2, R a and R b is hydrogen or —C 1-4 alkyl, and the asterisk * refers to the position attached to Ring A.
  • L b is *—C(O)—NH—CH 2 — or *—C(O)—NH—CH(CH 3 )—; wherein the asterisk * refers to the position attached to Ring A.
  • Aspect 33 The compound according to Aspect 1, wherein y is 0 or 1 or 2, and R 1 is halogen or —C 1-8 alkyl or hydroxyl-C 1-8 alkyl-, preferably fluoro, chloro, methyl or hydroxymethyl.
  • Aspect 34 The compound according to Aspect 1, wherein X b is CH and X c is N; or X b is N and X c is CH; or X b is CH and X c is CH.
  • Aspect 35 The compound according to Aspect 1, wherein X 1 is N and X a is CH; or X 1 is N and X a is N.
  • t is 0 or 1
  • R 2 is —C 1-8 alkyl, methoxy or halogen, preferably C 1-6 alkyl, more preferably methyl.
  • the compound according to Aspect 1 wherein X 1 is N and X a is CH; or X 1 is N and X a is N.
  • t is 0 or 1
  • R 2 is —C 1-8 alkyl, methoxy or halogen, preferably C 1-6 alkyl, more preferably methyl.
  • the substituent R 6 can be substituted at any available position in the
  • R 6 can be substituted at the atom Xa when Xa is CH.
  • Aspect 36 The compound according to Aspect 1, wherein the compound is selected from
  • a pharmaceutical composition comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • a method of decreasing BTK activity by inhibition and/or protein degradation which comprises administering to an individual the compound disclosed herein, or a pharmaceutically acceptable salt thereof, including the compound of formula (I) or the specific compounds exemplified herein.
  • a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof as a BTK kinase inhibitor and/or degrader, wherein the compound disclosed herein includes the compound of formula (I) or the specific compounds exemplified herein.
  • the disease or disorder is associated with inhibition of BTK.
  • the disease or disorder is cancer.
  • alkyl refers to a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.
  • alkyl groups comprising from 1 to 6 carbon atoms include without limitation to methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1, 1-dimethylethyl or t-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl
  • n-Pr 1-propyl or n-propyl
  • i-Pr 2-propyl or isopropyl
  • butyl refers to 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or s-butyl (“s-Bu”), 1, 1-dimethylethyl or t-butyl (“t-Bu”).
  • pentyl refers to 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.
  • hexyl refers to 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2, 3-dimethyl-2-butyl and 3, 3-dimethyl-2-butyl.
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).
  • haloalkyl refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo.
  • haloalkyl include without limitation to haloC 1-8 alkyl, haloC 1-6 alkyl or halo C 1-4 alkyl, such as —CF 3 , —CH 2 Cl, —CH 2 CF 3 , —CHCl 2 , —CF 3 , and the like.
  • alkenyl refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C ⁇ C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6, carbon atoms.
  • alkenyl group e.g., C 2-6 alkenyl
  • examples of the alkenyl group, e.g., C 2-6 alkenyl include without limitation to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1, 3-dienyl, 2-methylbuta-1, 3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl groups.
  • alkynyl refers to a hydrocarbon group selected from linear and branched hydrocarbon group, comprising at least one C ⁇ C triple bond and from 2 to 18, such as 2 to 8, further such as from 2 to 6, carbon atoms.
  • alkynyl group e.g., C 2-6 alkynyl
  • cycloalkyl refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.
  • the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
  • the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • examples of the saturated monocyclic cycloalkyl group include without limitation to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4, 4], [4, 5], [5, 5], [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane.
  • Further examples of the bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems.
  • spiro cycloalkyl refers to a cyclic structure which contains carbon atoms and is formed by at least two rings sharing one atom.
  • 7 to 12 membered spiro cycloalkyl refers to a cyclic structure which contains 7 to 12 carbon atoms and is formed by at least two rings sharing one atom.
  • fused cycloalkyl refers to a bicyclic cycloalkyl group as defined herein which is saturated and is formed by two or more rings sharing two adjacent atoms.
  • bridged cycloalkyl refers to a cyclic structure which contains carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.
  • 7 to 10 membered bridged cycloalkyl refers to a cyclic structure which contains 7 to 12 carbon atoms and is formed by two rings sharing two atoms which are not adjacent to each other.
  • cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.
  • the cycloalkenyl is cyclopentenyl or cyclohexenyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, preferably cyclohexenyl.
  • fused cycloalkenyl refers to a bicyclic cycloalkyl group as defined herein which contain at least one double bond and is formed by two or more rings sharing two adjacent atoms.
  • cycloalkynyl refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.
  • fused cycloalkynyl refers to a bicyclic cycloalkyl group as defined herein which contains at least one triple bond and is formed by two or more rings sharing two adjacent atoms.
  • a “benzo fused cycloalkyl” is a bicyclic fused cycloalkyl in which a 4- to 8-membered monocyclic cycloalkyl ring fused to a benzene ring.
  • a benzo fused cycloalkyl is
  • a “benzo fused cycloalkenyl” is a bicyclic fused cycloalkenyl in which a 4- to 8-membered monocyclic cycloalkenyl ring fused to a benzene ring.
  • a “benzo fused cycloalkynyl” is a bicyclic fused cycloalkynyl in which a 4- to 8-membered monocyclic cycloalkynyl ring fused to a benzene ring.
  • fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include but are not limited to bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, as well as benzo 3 to 8 membered cycloalkyl, benzo C 46 cycloalkenyl, 2, 3-dihydro-1H-indenyl, 1H-indenyl, 1, 2, 3, 4-tetralyl, 1, 4-dihydronaphthyl, etc.
  • Preferred embodiments are 8 to 9 membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms within the above examples.
  • aryl used alone or in combination with other terms refers to a group selected from:
  • aromatic hydrocarbon ring and “aryl” are used interchangeable throughout the disclosure herein.
  • a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl).
  • Examples of a monocyclic or bicyclic aromatic hydrocarbon ring include without limitation to phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like.
  • the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or phenyl ring.
  • the aromatic hydrocarbon ring is a phenyl ring.
  • bicyclic fused aryl refers to a bicyclic aryl ring as defined herein.
  • the typical bicyclic fused aryl is naphthalene.
  • heteroaryl refers to a group selected from:
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides.
  • bicyclic fused heteroaryl refers to a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein.
  • a bicyclic fused heteroaryl is 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, or 6-membered/7-membered bicyclic.
  • the group can be attached to the remainder of the molecule through either ring.
  • bicyclic fused heteroaryl include without limitation to the following groups: benzisoxazolyl, benzodiazolyl, benzofuranyl, benzofurazanyl, benzofuryl, benzoimidazolyl, benzoisothiazolyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxadiazolyl, benzoxazolyl, furopyridinyl, furopyrrolyl, imidazopyridinyl, imidazopyridyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzofuryl, isoindolyl, isoquinolinyl (or isoquinolyl), naphthyridinyl, phthalazinyl, pteridinyl, purinyl, pyrazinopyridazinyl,
  • a “benzo fused heteroaryl” is a bicyclic fused heteroaryl in which a 5- to 7-membered (preferably, 5- or 6-membered) monocyclic heteroaryl ring as defined herein fused to a benzene ring.
  • a monocyclic or bicyclic aromatic heterocyclic ring has 5-, 6-, 7-, 8-, 9- or 10-ring forming members with 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O) and the remaining ring members being carbon.
  • the monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O).
  • the monocyclic or bicyclic aromatic heterocyclic ring is a 5- to 6-membered heteroaryl ring, which is monocyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S) and oxygen (O).
  • the monocyclic or bicyclic aromatic heterocyclic ring is an 8- to 10-membered heteroaryl ring, which is bicyclic and which has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring examples include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazolyl, indo
  • Heterocyclyl “heterocycle” or “heterocyclic” are interchangeable and refer to a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.
  • oxidized sulfur used herein refer to S, SO or SO 2 .
  • monocyclic heterocyclyl refers to monocyclic groups in which at least one ring member (e.g., 1-3 heteroatoms, 1 or 2 heteroatom(s)) is a heteroatom selected from nitrogen, oxygen or optionally oxidized sulfur.
  • a heterocycle may be saturated or partially saturated.
  • Exemplary monocyclic 4 to 9-membered heterocyclyl groups include without limitation to pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl,
  • spiro heterocyclyl refers to a 5 to 20-membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon.
  • a spiro heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a spiro heterocyclyl is 6 to 14-membered, and more preferably 7 to 12-membered.
  • a spiro heterocyclyl could be mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, and more preferably 4-membered/3-membered, 4-membered/4-membered, 3-membered/5-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl.
  • spiro heterocyclyls include without limitation to the following groups: 2, 3-dihydrospiro[indene-1, 2′-pyrrolidine] (e.g., 2, 3-dihydrospiro[indene-1, 2′-pyrrolidine]-1′-yl), 1, 3-dihydrospiro[indene-2, 2′-pyrrolidine] (e.g., 1, 3-dihydrospiro[indene-2, 2′-pyrrolidine]-1′-yl), azaspiro[2.4]heptane (e.g., 5-azaspiro[2.4]heptane-5-yl), 2-oxa-6-azaspiro[3.3]heptane (e.g., 2-oxa-6-azaspiro[3.3]heptan-6-yl), azaspiro[3.4]octane (e.g., 6-azaspiro[3.4]octane-6-yl), 2-oxa-6-azaxan
  • fused heterocyclyl refers to a 5 to 20-membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms (carbon and carbon atoms or carbon and nitrogen atoms) with another ring, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon.
  • One or more rings of a fused heterocyclic group may contain one or more double bonds, but the fused heterocyclic group does not have a completely conjugated pi-electron system.
  • a fused heterocyclyl is 6 to 14-membered, and more preferably 7 to 12-membered, or 7- to 10-membered. According to the number of membered rings, a fused heterocyclyl could be bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl. The group can be attached to the remainder of the molecule through either ring.
  • bicyclic fused heterocyclyl refers to a 7 to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused heterocyclyl as defined herein comprising two fused rings and comprising 1 to 4 heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members.
  • a bicyclic fused heterocyclyl is 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, or 6-membered/7-membered bicyclic fused heterocyclyl.
  • (bicyclic) fused heterocycles include without limitation to the following groups: octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3, 4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl, octahydro-benzo[b][1, 4]dioxin, indolinyl, isoindolinyl, benzopyranyl, dihydrothiazolopyrimidinyl, tetrahydroquinolyl, tetrahydroisoquinolyl (or tetrahydroisoquinolinyl), dihydrobenzofuranyl, dihydrobenzoxazinyl, dihydrobenzoimidazolyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzodioxolyl, benzodioxonyl, chromany
  • a “benzo fused heterocyclyl” is a bicyclic fused heterocyclyl in which a monocyclic 4 to 9-membered heterocyclyl as defined herein (preferably 5- or 6-membered) fused to a benzene ring.
  • bridged heterocyclyl refers to a 5 to 14-membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, comprising one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon.
  • One or more rings of a bridged heterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
  • a bridged heterocyclyl is 6 to 14-membered, and more preferably 7 to 10-membered.
  • a bridged heterocyclyl could be bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl.
  • Representative examples of bridged heterocyclyls include without limitation to the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[3.3.2]decyl.
  • At least one substituent includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met.
  • at least one substituent R 6d disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R 6d as disclosed herein.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
  • the term “substantially pure” as used herein means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer(s). In some embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer(s).
  • substituents found on such ring system may adopt cis and trans formations.
  • Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.
  • the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomers refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical or chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers and diastereomers can also be separated by the use of a chiral HPLC column.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • a single stereoisomer e.g., a substantially pure enantiomer
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology . New York: Marcel Dekker, Inc., 1993.
  • “Pharmaceutically acceptable salts” refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • a pharmaceutically acceptable salt thereof includes salts of at least one compound of Formula (I), and salts of the stereoisomers of the compound of Formula (I), such as salts of enantiomers, and/or salts of diastereomers.
  • administration when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administration and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic agent, binding compound, or by another cell.
  • subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
  • an effective amount refers to an amount of the active ingredient, such as compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
  • the “therapeutically effective amount” can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined herein, a disease or disorder in a subject.
  • the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • the pharmaceutical composition comprising the compound disclosed herein can be administrated via oral, inhalation, rectal, parenteral or topical route to a subject in need thereof.
  • the pharmaceutical composition may be a regular solid formulation such as tablets, powder, granule, capsules and the like, a liquid formulation such as water or oil suspension or other liquid formulation such as syrup, solution, suspension or the like; for parenteral administration, the pharmaceutical composition may be solution, water solution, oil suspension concentrate, lyophilized powder or the like.
  • the formulation of the pharmaceutical composition is selected from tablet, coated tablet, capsule, suppository, nasal spray or injection, more preferably tablet or capsule.
  • the pharmaceutical composition can be a single unit administration with an accurate dosage.
  • the pharmaceutical composition may further comprise additional active ingredients.
  • compositions disclosed herein can be produced by the conventional methods in the pharmaceutical field.
  • the active ingredient can be mixed with one or more excipients, then to make the desired formulation.
  • the “pharmaceutically acceptable excipient” refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, for example: a diluent, a vehicle such as water, various organic solvents, etc., a filler such as starch, sucrose, etc., a binder such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone (PVP); a wetting agent such as glycerol; a disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; an absorption enhancer such as quaternary ammonium compound; a surfactant such as hexadecanol; an absorption carrier such as Kaolin and soap clay; a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc.
  • the pharmaceutical composition further comprises other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, an aromatic, a sweetener, a dye and etc.
  • other pharmaceutically acceptable excipients such as a decentralized agent, a stabilizer, a thickener, a complexing agent, a buffering agent, a permeation enhancer, a polymer, an aromatic, a sweetener, a dye and etc.
  • disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition”.
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 , and the like.
  • the subject compounds and pharmaceutically acceptable salts thereof can be prepared from (a) commercially available starting materials (b) known starting materials which may be prepared as described in literature procedures (c) new intermediates described in the schemes and experimental procedures herein.
  • the order of synthetic steps may be varied to increase the yield of desired product.
  • I-3 could be synthesized from I-1 and I-2 in the presence of metal catalyst in the basic condition, then I-3 was coupled with I-4 in basic condition and also with metal as catalyst to form I-5. Then the protective group was removed in acid condition to give I-6, which was converted to compound I with SN2 reaction, or reductive amination, or coupling reaction.
  • reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe; and glassware was oven dried and/or heat dried.
  • Preparative HPLC was conducted on a column (150 ⁇ 21.2 mm ID, 5 pm, Gemini NXC 18) at a flow rate of 20 ml/min, injection volume 2 ml, at room temperature and UV Detection at 214 nm and 254 nm.
  • Example 1 5-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine
  • Step 2 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 3 tert-butyl 5-bromo-3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate
  • Step 4 tert-butyl 5-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)-3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate
  • Step 5 5-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 6 5-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 To a solution of 5-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (25 mg, 0.04 mmol) and 3-(4-((2,6-dioxopiperidin-3-yl)amino)phenoxy)propyl methanesulfonate (23 mg, 0.06 mmol) in DMSO (2 mL) was added DIEA (17 mg, 0.12 mmol). The resulting mixture was heated at 90° C. overnight.
  • Step 1 N-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 2 tert-butyl 4-(4-(3-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate
  • Step 3 3-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 4 3-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 1 A mixture of 3-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (192 mg, 0.35 mmol) and 2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)acetaldehyde (100 mg, 0.32 mmol) in dichloromethane (20 mL) was stirred in a round bottom flask at room temperature for 1 hour.
  • Step 1 tert-butyl 5-bromo-3-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate
  • Step 2 tert-butyl 3-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-methylphenyl)-5-(4-(2-hydroxyethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate
  • Step 3 3-(tert-butyl)-N-(4-(5-(4-(2-hydroxyethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 4 3-(tert-butyl)-N-(2-methyl-4-(5-(4-(2-oxoethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 5 3-(tert-butyl)-N-(4-(5-(4-(2-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-1-yl)ethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 10 3-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 1 N-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 2 tert-butyl 4-(4-(3-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate
  • Step 3 3-(tert-butyl)-N-(2-fluoro-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride
  • Step 4 3-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 11 3-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 1 N-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 2 tert-butyl 4-(4-(3-(4-((3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)methyl)-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate
  • Step 3 3-(tert-butyl)-N-(2-fluoro-4-(5-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide bi-hydrochloride
  • Step 4 3-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 12 3-(tert-butyl)-N-(4-(5-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 13 3-(tert-butyl)-N-(4-(5-(4-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 15 5-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 5-(tert-butyl)-N-(2-fluoro-4-(5-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride
  • Step 2 5-(tert-butyl)-N-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 16 3-(tert-butyl)-N-(4-(5-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 17 3-(tert-butyl)-N-(4-(5-(4-(4-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 18 3-(tert-butyl)-N-(4-(5-(4-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 1 3-(2,4-dioxotetrahydropyrimidin-1(2H-yl) 4 -methoxybenzoic acid
  • Step 2 3-(tert-butyl)-N-(4-(5-(4-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 20 3-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 22 5-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 24 3-(tert-butyl)-N-(4-(5-(4-(1-(3-(4-((2,6-dioxopiperidin-3-yl)amino)-3-methylphenoxy)propyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 25 3-(tert-butyl)-N-(4-(5-(4-(1-(2-(4-(2,6-dioxopiperidin-3-yl)naphthalen-1-yl)ethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 28 3-(tert-butyl)-N-(4-(5-(4-(1-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)piperidin-4-yl)ethyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 31 1-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide
  • Step 1 N-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamide
  • Step 2 tert-butyl 4-(4-(3-(4-((1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)methyl)-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate
  • Step 3 1-(tert-butyl)-N-(2-methyl-4-(5-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide hydrochloride
  • Step 4 1-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide
  • Example 32 1-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide
  • Example 33 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 34 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 36 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 40 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 48 5-(tert-butyl)-N-(4-(5-(4-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 50 5-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenoxy)propyl methanesulfonate
  • Step 2 5-(tert-butyl)-N-(4-(5-(4-(4-(3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenoxy)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 53 3-(tert-butyl)-N-(4-(5-(4-(1-(3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)propyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 54 3-(tert-butyl)-N-(4-(5-(4-(1-(3-(4-(2,6-dioxopiperidin-3-yl)phenoxy)propyl)piperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 55 3-(tert-butyl)-N-(4-(5-(4-(4-(3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 56 3-(tert-butyl)-N-(4-(5-(6-(1-(3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)propyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 57 3-(tert-butyl)-N-(4-(5-(5-(1-(3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)propyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 58 3-(tert-butyl)-N-(4-(5-(4-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 59 3-(tert-butyl)-N-(4-(5-(4-(4-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 60 (S)-3-(tert-butyl)-N-(4-(5-(4-(4-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)-2-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 61 3-(tert-butyl)-N-(4-(5-(6-(4-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 62 3-(tert-butyl)-N-(4-(5-(5-(4-(2-(1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-fluorobenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 63 5-(tert-butyl)-N-(4-(5-(6-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 64 5-(tert-butyl)-N-(4-(5-(5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 65 5-(tert-butyl)-N-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 66 5-(tert-butyl)-N-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 67 3-(tert-butyl)-N-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 68 3-(tert-butyl)-N-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 69 5-(tert-butyl)-N-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 70 5-(tert-butyl)-N-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 72 (R)-5-(tert-butyl)-N-(1-(4-(5-(5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 74 (R)-5-(tert-butyl)-N-(1-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 75 (R)-3-(tert-butyl)-N-(1-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 76 (R)-3-(tert-butyl)-N-(1-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 77 (R)-5-(tert-butyl)-N-(1-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 78 (R)-5-(tert-butyl)-N-(1-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 80 (R)-5-(tert-butyl)-N-(1-(4-(5-(5-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 86 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(3-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenoxy)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 87 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 90 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 93 2-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)thiazole-4-carboxamide
  • Example 94 2-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)thiazole-5-carboxamide
  • Example 96 (R)—N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide
  • Example 100 5-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 101 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 102 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 103 5-(tert-butyl)-N-(4-(5-(5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 N-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 2 5-(tert-butyl)-N-(2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,24-oxadiazole-3-carboxamide
  • Step 3 tert-butyl 4-(6-(3-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)piperazine-1-carboxylate
  • Step 4 5-(tert-butyl)-N-(2-methyl-4-(5-(5-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 5 5-(tert-butyl)-N-(4-(5-(5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 104 (R)—N-(1-(4-(5-(4-(4-(2-(1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide
  • Example 105 3-(tert-butyl)-N-(4-(5-(6-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 106 3-(tert-butyl)-N-(4-(5-(6-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 107 5-(tert-butyl)-N-(4-(5-(4-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 108 1-(tert-butyl)-N-(4-(5-(4-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide
  • Example 109 (R)—N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 111 and 112 5-(tert-butyl)-N—((R)-1-(4-(5-(4-(4-(4-(4-((R)-2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N—((R)-1-(4-(5-(4-(4-(4-(4-((S)-2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 113 and 114 5-(tert-butyl)-N—((R)-1-(4-(5-(4-(4-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N—((R)-1-(4-(5-(4-(4-(4-(4-((S)-2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadia
  • Example 115 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(3-chloro-4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 116 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 N-((1R)-1-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 2 5-(tert-butyl)-N-((1R)-1-(2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 3 tert-butyl 4-(6-(3-(4-((R)-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)piperazine-1-carboxylate
  • Step 4 (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(5-(5-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 5 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 117 5-(tert-butyl)-N-((1R)-1-(4-(5-(6-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 tert-butyl 5-chloro-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate
  • Step 2 tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate
  • Step 3 tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperidine-1-carboxylate
  • Step 4 tert-butyl 4-(5-(3-(4-((R)-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)ethyl)-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-2-yl)piperidine-1-carboxylate
  • Step 5 (R)-5-(tert-butyl)-N-(1-(2-methyl-4-(5-(6-(piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride
  • Step 6 5-(tert-butyl)-N-((1R)-1-(4-(5-(6-(1-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 118 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(4-(3-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenoxy)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 120 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)-3-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 121 5-(tert-butyl)-N-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(hydroxymethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 122 (R)-5-(tert-butyl)-N-(1-(4-(5-(5-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 123 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-((2,6-dioxopiperidin-3-yl)oxy)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 124 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidine-4-carbaldehyde
  • Step 2 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 125 1-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1H-1,2,3-triazole-4-carboxamide
  • Example 127 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 128 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(2-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)ethyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 129 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 130 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)-3-methoxyphenoxy)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 131 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-((2,6-dioxopiperidin-3-yl)amino)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 132 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 133 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-(4-(2,6-dioxopiperidin-3-yl)phenethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 134 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-fluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 135 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 136 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(1-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 137 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)-3-methoxyphenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 138 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 139 and 140 5-(tert-butyl)-N—((R)-1-(4-(5-(4-(4-(2-(5-((S)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N—((R)-1-(4-(5-(4-(4-(2-(5-((R)-2,6-dioxopiperidin-3-yl)pyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-ox
  • Example 139 This resulted in Example 139 (29.8 mg, the first isomer) and Example 140 (26.6 mg, the second isomer).
  • Example 141 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 142 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(3-(4-((2,6-dioxopiperidin-3-yl)amino)-3-fluorophenoxy)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 143 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 144 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 145 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(1-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)piperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 146 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 147 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 148 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 149 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 150 and 151 (R)-1-(tert-butyl)-N-(4-(5-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide and (S)-1-(tert-butyl)-N-(4-(5-(4-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide
  • the first enantiomer Example 150 was eluted at the retention time of 1.441 min, and the other enantiomer Example 151 was eluted at the retention time of 1.946 min.
  • Example 152 and 153 5-(tert-butyl)-N—((R)-1-(4-(5-(6-(1-(4-((R)-2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N—((R)-1-(4-(5-(6-(1-(4-((S)-2,6-dioxopiperidin-3-yl)phenethyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • the first enantiomer Example 152 was eluted at the retention time of 0.992 min, and the other enantiomer Example 153 was eluted at the retention time of 1.265 min.
  • Example 154 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 155 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 156 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 157 (R)-5-(tert-butyl)-N-(1-(4-(6-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 158 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 159 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(2-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 160 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)propyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 161 and 162 5-(tert-butyl)-N—((R)-1-(4-(5-(5-(4-(4-((S)-2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N—((R)-1-(4-(5-(5-(4-(4-((R)-2,6-dioxopiperidin-3-yl)phenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 163 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 164 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 1 1-(1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 2 2-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethyl methanesulfonate
  • Step 3 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(2-(4-(2,4-dioxo-3-((2-(trimethylsilyl)ethoxy)methyl)tetrahydropyrimidin-1(2H)-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 4 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(2-(4-(3-(hydroxymethyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Step 5 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-(2-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 165 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((4-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 166 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-fluoro-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 167 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 168 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 169 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(1-(4-(2,6-dioxopiperidin-3-yl)-3-methoxyphenyl)piperidin-4-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 170 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 171 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-2-methoxyphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 172 (R)-5-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)isoxazole-3-carboxamide
  • Example 173 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-(2-(5-(2,6-dioxopiperidin-3-yl)-4-methylpyridin-2-yl)ethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 174 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-(4-(2,6-dioxopiperidin-3-yl)phenethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 175 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 176 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide formate
  • Example 177 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 178 (R)-5-(tert-butyl)-N-(1-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 179 (R)-5-(tert-butyl)-N-(1-(4-(5-(6-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 180 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(1-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 181 and 182 5-(tert-butyl)-N—((R)-1-(4-(5-(5-(4-(4-((R)-2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N—((R)-1-(4-(5-(5-(4-(4-((S)-2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-o
  • Example 183 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-((4-(2,6-dioxopiperidin-3-yl)phenoxy)methyl)piperidin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 184 (R)—N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-5-(1-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 185 (R)—N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-5-(1-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 186 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 188 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,2-difluoroethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 189 5-(tert-butyl)-N-((1R)-1-(4-(5-(5-(5-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methylpyridin-2-yl)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 190 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-fluoro-2-(hydroxymethyl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 191 5-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-((1-(4-(2,6-dioxopiperidin-3-yl)phenyl)pyrrolidin-3-yl)methyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 192 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2,2-difluoroethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 195 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(5-(2,6-dioxopiperidin-3-yl)-6-methoxypyridin-2-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 196 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(2-(4-(2,6-dioxopiperidin-3-yl)-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 197 5-(tert-butyl)-N-((1R)-1-(4-(5-(6-(1-(3-(4-(2,6-dioxopiperidin-3-yl)phenyl)cyclobutyl)piperidin-4-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 199 5-(tert-butyl)-N-((1R)-1-(4-(5-(6-(4-(4-(2,6-dioxopiperidin-3-yl)-3-fluorophenethyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide
  • Example 200 3-(tert-butyl)-N-((1R)-1-(4-(5-(4-(4-(4-(4-(4-(2,5-dioxopyrrolidin-3-yl)phenethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 201 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 1 tert-butyl 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate
  • Step 2 tert-butyl 4-(4-(3-(4-((R)-1-(3-(tert-butyl)-1,2,4-oxadiazole-5-carboxamido)ethyl)-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)-4-hydroxypiperidine-1-carboxylate
  • Step 3 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(4-hydroxypiperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride
  • Step 4 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 202 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(4-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-1,4-diazepan-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 203 (R)-3-(tert-butyl)-N-(1-(4-(5-(4-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 204 (R)-3-(tert-butyl)-N-(1-(4-(5-(5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-hydroxypiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Example 205 (R)-3-(tert-butyl)-N-(1-(4-(5-(5-(1-((1-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)methyl)-4-fluoropiperidin-4-yl)pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-methylphenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide
  • Step 1 tert-butyl 4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate
US17/910,037 2020-03-11 2021-03-10 Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use Pending US20230322761A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CN2020078884 2020-03-11
WOPCT/CN2020/078884 2020-03-11
CN2021076294 2021-02-09
WOPCT/CN2021/076294 2021-02-09
PCT/CN2021/079882 WO2021180103A1 (fr) 2020-03-11 2021-03-10 Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et procédés d'utilisation

Publications (1)

Publication Number Publication Date
US20230322761A1 true US20230322761A1 (en) 2023-10-12

Family

ID=77672122

Family Applications (1)

Application Number Title Priority Date Filing Date
US17/910,037 Pending US20230322761A1 (en) 2020-03-11 2021-03-10 Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use

Country Status (4)

Country Link
US (1) US20230322761A1 (fr)
CN (1) CN115335376A (fr)
TW (1) TW202140478A (fr)
WO (1) WO2021180103A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022143856A1 (fr) * 2020-12-31 2022-07-07 Beigene, Ltd. Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et procédés d'utilisation
EP4359403A1 (fr) * 2021-06-21 2024-05-01 BeiGene Switzerland GmbH Ligands de (r)-glutarimide crbn et procédés d'utilisation
US11976071B2 (en) 2021-08-18 2024-05-07 Gilead Sciences, Inc. Substituted pyrrolo[1,2-b]pyridazines as bifunctional degraders of interleukin-1 receptor-associated kinases
WO2023125908A1 (fr) * 2021-12-30 2023-07-06 Beigene, Ltd. Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et procédés d'utilisation
WO2023227080A1 (fr) * 2022-05-25 2023-11-30 百极弘烨(南通)医药科技有限公司 Composé protac, composition pharmaceutique le contenant, son procédé de préparation et son utilisation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2009010284A (es) * 2007-03-28 2010-01-29 Pharmacyclics Inc Inhibidores de la tirosina-cinasa de bruton.
MX2011000661A (es) * 2008-07-16 2011-05-25 Pharmacyclics Inc Inhibidores de tirosina cinasa de bruton para el tratamiento de tumores solidos.
CA2959602A1 (fr) * 2014-08-01 2016-02-04 Pharmacyclics Llc Inhibiteurs de la tyrosine kinase de bruton
TW202016109A (zh) * 2018-06-13 2020-05-01 英屬開曼群島商百濟神州有限公司 作為hpk1抑制劑的吡咯並[2,3-b]吡啶或吡咯並[2,3-b]吡嗪及其用途

Also Published As

Publication number Publication date
TW202140478A (zh) 2021-11-01
WO2021180103A1 (fr) 2021-09-16
CN115335376A (zh) 2022-11-11

Similar Documents

Publication Publication Date Title
US20220281876A1 (en) Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use
US20220267354A1 (en) Tricyclic compounds as hpk1 inhibitor and the use thereof
US20220267333A1 (en) PYRROLO[2,3-b]PYRAZINES AS HPK1 INHIBITOR AND THE USE THEREOF
US20230322761A1 (en) Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inhibitors with e3 ligase ligand and methods of use
WO2020103896A1 (fr) Pyrrolo[2,3-b]pyridines utilisés en tant qu'inhibiteur de hpk1 et leurs utilisations
US20230322788A1 (en) Imidazotriazine and pyrrolopyrimidine derivatives as kras g12c inhibitors
US20220289712A1 (en) Aminopyrazine compounds as hpk1 inhibitor and the use thereof
US20230265116A1 (en) Degradation of (egfr) by conjugation of egfr inhibitors with e3 ligase ligand and methods of use
US20230002369A1 (en) Bcl-2 INHIBITORS
US20230248834A1 (en) Degradation of (egfr) by conjugation of egfr inhibitors with e3 ligase ligand and methods of use
US20230167118A1 (en) Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inidbitors with e3 ligase ligand and methods of use
US20240092803A1 (en) Bridged compounds as kras g12d inhibitor and degrader and the use thereof
WO2023006063A1 (fr) Composés bifonctionnels à base de pyrrolo [2, 3-b] pyrazine utilisés comme agents de dégradation de la hpk1 et leur utilisation
WO2021170046A1 (fr) Inhibiteur de tyk-2
WO2022152233A1 (fr) Inhibiteurs de kras g12c
WO2023125907A1 (fr) Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et méthodes d'utilisation
US20230373963A1 (en) 3-[(1h-pyrazol-r-yl)oxy]pyrazin-2-amine compounds as hpk1 inhibitor and use thereof
WO2023125908A1 (fr) Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et procédés d'utilisation
WO2023098656A1 (fr) Composés pour la dégradation de la kinase egfr
WO2023237049A1 (fr) Dégradation d'irak4 par conjugaison d'inhibiteurs d'irak4 avec un ligand de ligase e3 et procédés d'utilisation
WO2024099395A1 (fr) Composés utilisés dans la dégradation de la kinase egfr
WO2022143856A1 (fr) Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et procédés d'utilisation

Legal Events

Date Code Title Description
AS Assignment

Owner name: BEIGENE, LTD., CAYMAN ISLANDS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WANG, HEXIANG;LEI, BAILIN;HUO, CHANGXIN;AND OTHERS;SIGNING DATES FROM 20210705 TO 20210809;REEL/FRAME:063547/0365

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION